Osteoimmunity-Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration

Area of Science:

• Biomaterials Science
• Tissue Engineering
• Immunomodulation
• Bone Regeneration

Background:

• Effective bone tissue regeneration requires precise control over the immune response post-biomaterial implantation.
• Existing strategies often struggle to balance pro-regenerative and anti-inflammatory signals.
• A hierarchical scaffold integrating immunomodulatory and osteogenic cues is needed for enhanced bone repair.

Purpose of the Study:

• To fabricate a biomimetically hierarchical scaffold for augmenting bone repair by balancing immune response and bone metabolism.
• To investigate the scaffold's ability to modulate macrophage phenotype, promote angiogenesis, and enhance osteogenesis.
• To evaluate the in vitro and in vivo efficacy of the osteoimmunity-regulating scaffold for large-scale bone defect repair.

Main Methods:

• Fabrication of a 3D printed scaffold combining deferoxamine@poly(ε-caprolactone) nanoparticles (DFO@PCL NPs), manganese carbonyl (MnCO) nanosheets, gelatin methacryloyl hydrogel, and a polylactide/hydroxyapatite (HA) matrix.
• Utilized a Fenton-like reaction for controlled release of carbon monoxide and Mn²⁺ from MnCO nanosheets.
• Assessed immunomodulatory effects by analyzing macrophage polarization (M2 phenotype) and vascular endothelial growth factor (VEGF) secretion.
• Investigated the role of Mn²⁺ and DFO@PCL NPs in activating the hypoxia-inducible factor-1α (HIF-1α) pathway to promote angiogenesis.
• Evaluated osteoclast differentiation inhibition by DFO and osteogenic activity synergy with HA.
• Performed in vitro and in vivo experiments to assess overall bone regeneration efficacy.

Main Results:

• The scaffold successfully mimicked bone tissue structure and extracellular matrix properties.
• MnCO nanosheets triggered a Fenton-like reaction, releasing CO and Mn²⁺ to reduce inflammation by upregulating M2 macrophages.
• Upregulated M2 macrophages secreted VEGF, promoting vascular formation.
• Mn²⁺ and DFO@PCL NPs activated the HIF-1α pathway, enhancing angiogenesis.
• DFO inhibited osteoclast differentiation, while HA exhibited osteoinductive activity, showing synergistic effects.
• The scaffold demonstrated strong immunomodulatory, angiogenic, and osteogenic properties with weak osteoclastogenic potential.

Conclusions:

• The developed osteoimmunity-regulating scaffold significantly improves bone regeneration by harmonizing immune responses and bone metabolism.
• This biomaterial presents a promising strategy for addressing large-scale bone defects through its multi-faceted regenerative capabilities.
• The findings provide a valuable foundation and positive outlook for future advancements in bone defect repair.